title: Early administration of high-dose antithrombin in severe sepsis: single center results from the KyberSept-trial.
abstract: BACKGROUND
  The overall finding in the KyberSept trial of no treatment effect of high-dose antithrombin (AT) in severe sepsis was inconsistent for the primary outcome, 28-day mortality, possibly because of patient heterogeneity. No data have been reported on the effects of AT therapy administered early in severe sepsis when microcirculation is disturbed but irreversible organ damage has not yet developed.
  
  
  OBJECTIVE
  We report the post hoc results of the KyberSept trial in patients with severe sepsis treated at a single center early after new onset organ failure.
  
  
  METHODS
  All study participants from a United States tertiary care intensive care unit were analyzed. Patients had been randomized 1:1 (placebo: n = 41; AT: n = 40) to receive AT (30,000 IU IV over a period of four days) or placebo within 48 h.
  
  
  RESULTS
  Baseline variables were well balanced between groups. Eighty percent of patients (n = 65) received study drug within 24 h after onset of severe sepsis; 94% (n = 76) received study drug within 48 h. Nine of 40 participants in the AT group (22.5%) had new organ dysfunction during the first 7 days which was not present at baseline compared with 17 of 39 subjects (43.6%) in the placebo group (P = 0.058; two participants had dysfunction of all organs at baseline and were therefore excluded). At 28 days, 16 of 40 patients (40%) treated with AT died versus 22 of 41 (54%) with placebo [absolute reduction, 14%; odds ratio (95% confidence interval), 0.58 (0.24-1.39)]. In patients receiving AT, a significantly increased bleeding incidence was observed (any bleeding, 8 of 40 (20.0%) for AT group vs 1/41 (2.4%) for placebo group; P < 0.015).
  
  
  CONCLUSIONS
  Data from this post hoc analysis confirm an increased bleeding risk seen with AT treatment in these patients. When given early in severe sepsis, though statistically not significant, absolute risk reductions with AT of 21% and 14% for organ failure and mortality, respectively, indicate a potential for treatment benefit in selected sepsis patients. This observation may have implications for continuing sepsis trials with AT that focus on reduced patient heterogeneity.
authors.affiliation: Division of Pulmonary and Critical Care, CO Springs Memorial Hospital, CO Springs, Colorado, USA.
authors.forename: Alain
authors.initials: A
authors.lastname: Eid
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Wiedermann
authors.forename: Gary T
authors.initials: GT
authors.lastname: Kinasewitz
mesh_terms: D018806:APACHE; D000328:Adult; D000368:Aged; D000991:Antithrombins / Q000627:therapeutic use*; D001794:Blood Pressure; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006339:Heart Rate; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009102:Multiple Organ Failure / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control; D040242:Risk Reduction Behavior; D018805:Sepsis / Q000150:complications / Q000188:drug therapy* / Q000453:epidemiology; D016019:Survival Analysis; D017741:Survivors
chemical_list: D000991:Antithrombins